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Sci Rep. 2017 Apr 5;7:45617. doi: 10.1038/srep45617.

HPV positive neuroendocrine cervical cancer cells are dependent on Myc but not E6/E7 viral oncogenes.

Author information

1
Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.
2
Department of Oncology, Georgetown University Medical School, Washington DC, 20057, USA.
3
College of Pharmacy, King Abulaziz University, Jeddah, Saudi Arabia.
4
Human Cancer Genetics Program and Dept. of Molecular Virology, Immunology and Medical Genetics, Ohio State University Comprehensive Cancer Center, USA.
5
Dept. of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
6
Cancer Genomics Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

Abstract

Using conditional cell reprogramming, we generated a stable cell culture of an extremely rare and aggressive neuroendocrine cervical cancer. The cultured cells contained HPV-16, formed colonies in soft agar and rapidly produced tumors in immunodeficient mice. The HPV-16 genome was integrated adjacent to the Myc gene, both of which were amplified 40-fold. Analysis of RNA transcripts detected fusion of the HPV/Myc genes, arising from apparent microhomologous recombination. Spectral karyotyping (SKY) and fluorescent-in-situ hybridization (FISH) demonstrated coordinate localization and translocation of the amplified Myc and HPV genes on chromosomes 8 and 21. Similar to the primary tumor, tumor cell cultures expressed very high levels of the Myc protein and, in contrast to all other HPV-positive cervical cancer cell lines, they harbored a gain-of-function mutation in p53 (R273C). Unexpectedly, viral oncogene knockdown had no effect on the growth of the cells, but it did inhibit the proliferation of a conventional HPV-16 positive cervical cancer cell line. Knockdown of Myc, but not the mutant p53, significantly inhibited tumor cell proliferation. On the basis of these data, we propose that the primary driver of transformation in this aggressive cervical cancer is not HPV oncogene expression but rather the overexpression of Myc.

PMID:
28378747
PMCID:
PMC5381214
DOI:
10.1038/srep45617
[Indexed for MEDLINE]
Free PMC Article

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